Intracellular pH Regulation in Ventricular Myocytes: Implications for Cardiac Health and Disease

Abstract

Intracellular pH must be maintained within the physiological range (7.15-7.25) to ensure cellular homeostasis. In the heart, excitation-contraction coupling is closely dependent on intracellular pH because its proper regulation helps the correct management of intracellular Ca²⁺. In addition, it is important to know the spatial distribution of intracellular pH microdomains because it helps us to better understand the compartmentalized regulation of different channels, transporters, and enzymes. Therefore, maintaining cardiac intracellular pH at physiological levels is of crucial importance for cardiac health. This function is performed by transporters and channels that ensure the transport of H⁺ equivalents to both sides of the sarcolemma. In the cardiac myocyte, 3 alkalizing mechanisms are expressed in the sarcolemma, the NHE1 (Na⁺/H⁺ exchanger 1), the NBC (Na⁺/HCO₃^- cotransporter, represented by 2 different isoforms; NBCn1 [electrically neutral sodium/bicarbonate cotransporter 1] and NBCe1 [electrogenic sodium/bicarbonate cotransporter 1]), and a proton channel (HVCN1 [hydrogen voltage-gated proton channel 1]; IH⁺), and 2 acidifying transporters, the Cl^-/HCO₃^- exchanger (AE [anion exchanger], mainly AE1, AE2, and AE3) and Slc26a6 (solute carrier family 26 member A6), which, in the heart, predominantly exchanges Cl^-/HCO₃^- and Cl^-/OH^-. The presence of a lactate-H⁺ cotransport (MCT [monocarboxylate transporter]) has also been described, which operates in either efflux or influx mode. The overstimulation of NHE1 and NBCn1, and the dysfunction of NBCe1 have been associated with the development of maladaptive cardiac hypertrophy. On the other hand, the sudden stimulation of these transporters, which occurs during reperfusion after ischemia, greatly contributes to the cardiac injury of this insult to the myocardium. The alteration of the normal functioning of the acidifying mechanisms has also been implicated in these pathologies. This review focuses on the role that these mechanisms play in healthy and diseased hearts.

Keywords: cardiac hypertrophy; cardiac myocytes; intracellular pH; myocardial ischemia; transporters.